The Nature of Persistent Conformational Chirality, Racemization Mechanisms, and Predictions in Diarylether Heptanoid Cyclophane Natural Products

Restricted rotations of chemical bonds can lead to the presence of persistent conformational chirality in molecules 10 lacking stereocenters. We report the development of first-ofa- kind predictive rules that enable identification of conformational chirality and prediction of racemization barriers in the diarylether heptanoid (DAEH) natural products that do not possess stereocenters. These empirical 15 rules-of-thumb are based on quantum mechanical computations (SCS-MP2/∞//B3LYP/6-31G*/PCM) of racemization barriers of four representative DAEHs. Specifically, the local symmetry of ring B and the E/Z configuration of the vinylogous acid/ester are critical in 20 determining conformational chirality in the DAEH natural product family. Molecular chirality is of paramount importance to chemistry, biology, and medicine. Small molecules that are chiral by virtue of restricted rotations (atropisomerism), or conformational 25 chirality, are an underdeveloped territory with the potential for new developments of chiral ligands, medicinal compounds, catalysts, and materials. At present, there are no known methods to predict the presence of persistent conformational chirality in these compounds based solely on their molecular architecture 30 without resorting to total synthesis. Specifically in this report, we have developed predictive rules-of-thumb for the chiral properties of all members in a family of cyclophane natural products called the diarylether heptanoids (DAEHs). Additionally, we elucidate the atomistic and energetic details 35 related to the racemizations.This is an author's peer-reviewed final manuscript, as accepted by the publisher

Conformationally chiral diphenylethers and the enantioselective Ullmann etherification

Since the discovery of molecular chirality in 1848, this notion has had a substantial impact on medicine, biology, and chemistry. Extensive effort has been directed towards the construction of chiral molecules that contain sp³ hybridized stereogenic centers. In contrast, less effort has been dedicated to molecules that are chiral by virtue of their conformation. Nevertheless, structures with restricted rotation of sigma bonds including biaryls, cyclophanes, allenes and strained cyclic alkenes have attracted plentiful attention as chiral ligands, catalysts, synthetic intermediates and targets of total synthesis We believe that conformational chirality is more prevalent than commonly believed and goes undetected in many natural products that do not contain sp³ hybridized stereogenic centers. This thesis contains a body of work that provides a better understanding of conformationally chiral molecules. The ability to identify the existence of conformational chirality in complex molecular architectures devoid of stereogenic centers along with methods to access them is described. Toward this end, we sought to study a family of molecules with conserved molecular architectures, devoid of stereogenic centers, that sometimes (but not always) display chirality. The aim is to develop experimental tools to determine which members are chiral and achiral and to develop a structure chirality relationship. The diarylether heptanoid (DAEH) natural products fit these criteria, and they were selected as an excellent platform to study chirality in diphenylethers. The exploration begins with the synthesis and chiral properties of the heptanone DAEHs. A unified route was developed to access all heptanone DAEH members. The synthetic material was used to measure their optical activities and free energy of activation for racemization. The natural enantiomers of myricatomentogenin, jugcathanin, galeon, and pterocarine were determined to have the same pR absolute stereochemistry. Acerogenins L and C are achiral compounds. The remaining DAEHs members, which are the garuganins and garugamblins were synthesized and their chiral properties were determined. Alkene stereoisomers, vinylogous ester regioisomers, and β-diketone congeners werse also synthesized. The chiral properties and free energies of activation for racemization of the garuganin and garugamblin DAEHs and congeners were determined using dynamic NMR methods. A combination of techniques including coalescence measurements, lineshape analysis, and selective inversion experiments are used to measure racemization barriers. None of the garuganin or garugamblin diarylether heptanoids are chiral, despite being isolated as optically active compounds. The first enantioselective Ullmann cross-coupling reactions to prepare diaryl ethers are reported. Upon completing the syntheses of the DAEHs and determining their chirality, we find only four members to be chiral. Our effort to access enantiopure material was accomplished by rendering the Ullmann reaction enantioselective by using N-methyl proline as the chiral ligand. This reaction was used to prepare all the chiral diarylether heptanoid natural products, which are (–)-myricatomentogenin, (–)-jugcathanin, (+)-galeon, and (+)-pterocarine. The first synthesis of russuphelol was accomplished, and its chiral properties were investigated. We have applied our knowledge of conformational chirality from the DAEH system to an acyclic triphenylether russuphelol. The synthesis of the natural product has been accomplished in six steps. Despite the optical activity reported upon isolation, we find russuphelol to have no element of chirality. As a result of the work presented in this thesis we better understand conformational chirality in diphenylethers. Tools to examine, identify, and measure molecular chirality where no stereocenters are present were developed. This contribution will benefit the chemical community in many areas such as catalysis, natural productss isolation and medicine. In conclusion, all fifteen members of the DAEH family have been synthesized, and determined which members of this family are chiral. This knowledge was then utilized in the investigation of chirality in the acyclic diphenylether russuphelol, which had a mistaken identity of chirality when isolated. Development of the first enantioselective Ullmann coupling reaction to construct C–O bonds and its use in the first enantioselective synthesis of all chiral DAEHs is reported. With all the knowledge we have created we hope to increase the understanding of molecular chirality in the greater scientific community

Enantioselective Ullmann Ether Couplings: Syntheses of (−)-Myricatomentogenin, (−)-Jugcathanin, (+)-Galeon, and (+)-Pterocarine

The first enantioselective Ullmann cross-coupling reactions to prepare diaryl ethers are reported. The reactions were used to prepare the diarylether heptanoid natural products (−)-myricatomentogenin, (−)-jugcathanin, (+)-galeon, and (+)-pterocarine

Chirality in Diarylether Heptanoids: Synthesis of Myricatomentogenin, Jugcathanin, and Congeners

The syntheses of myricatomentogenin, jugcathanin, galeon, pterocarine, and acerogenin L are reported. Synthetic material was used to measure their optical activities and free energy of activation for racemization. The natural enantiomers of myricatomentogenin, jugcathanin, galeon, and pterocarine were determined to have the same p<i>R</i> absolute stereochemistry. Acerogenins L and C are achiral compounds

Total Synthesis of Russuphelol: A Case of Mistaken Chirality

The chlorohydroquinone tetramer, russuphelol, does not have stereocenters; however, it was reported as a chiral optically active substance with stable enantiomeric conformations. The natural product is synthesized in six steps and 14% overall yield. Synthetic material was used to experimentally investigate its chiral properties

The Garuganin and Garugamblin Diarylether Heptanoids: Total Synthesis and Determination of Chiral Properties Using Dynamic NMR

The synthesis of the garuganin and garugamblin diarylether heptanoids using an intramolecular Ullmann coupling is reported. Alkene stereoisomers, vinylogous ester regioisomers, and β-diketone congeners are also synthesized. The chiral properties and free energies of activation for racemization of the garuganin and garugamblin diarylether heptanoids and congeners are determined using dynamic NMR methods. A combination of techniques including coalescence measurements, line shape analysis, and selective inversion experiments are used to measure racemization barriers. None of the garuganin or garugamblin diarylether heptanoids are chiral, despite their reported specific rotation values